While diagnostic criteria for typical multiple sclerosis (MS) perform well in people ages 18 to 50, differential diagnoses in pediatric-onset MS and late-onset MS require specific considerations.
“Recognizing red flags that suggest other common diseases can help with accurate identification of MS versus its mimics,” said Le Hua, MD, director of the Mellen Program for Multiple Sclerosis at the Cleveland Clinic in Las Vegas, Nevada.
“For children, progressive MS is extremely rare, so gradual accumulation of disability would prompt another diagnosis such as metabolic disorders,” Hua told MedPage Today.
“For late-onset MS, vascular diseases are the most common mimic and reason for MS misdiagnosis as they can also cause accumulation of white matter lesions over time, in particular small vessel disease or migraine vasculopathy,” she said.
Characteristics of Pediatric and Late-Onset Disease
Both pediatric- and late-onset MS are much less common than typical adult-onset disease. Onset of MS before age 18 occurs in up to 10% of MS patients, while onset after age 50 occurs in about 5%.
Children and adolescents with MS have higher annualized relapse rates and higher MRI inflammatory disease activity at onset compared with patients who have onset at typical ages. Children also reach MS disability milestones at younger ages from onset than typical MS patients. Even when they are relatively young, children with pediatric-onset MS have shown progression independent of relapse activity.
Adults with late-onset MS have more progressive disease than those with onset at typical MS ages, with significant neurodegeneration and infrequent inflammatory demyelination. This group has a lower proportion of women, a higher proportion of primary progressive MS, a higher level of disability at diagnosis, and a higher proportion of gait-related initial symptoms than patients with MS at typical ages.
Diagnosing Pediatric and Late-Onset MS
Biological differences in early- and late-onset age groups — especially immunological and hormonal variances — may influence the MS disease course and resilience to neuronal injury, an expert committee stated in a recent review published in JAMA Neurology.
The review was prepared by an international panel of pediatric and adult MS experts (including Hua) to provide consensus guidance on diagnostic approaches for children and older adults. It relied on previously identified features of typical MS described in a 2023 consensus paper and updated earlier recommendations that were published in 2008.
Dilemmas in diagnosing pediatric-onset disease may include differentiating MS from acute monophasic disseminated encephalomyelitis (ADEM) or myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which share some clinical and imaging features with MS, the committee noted.
In young children with new central nervous system (CNS) demyelination, advanced imaging techniques may help identify differences in MS and MOGAD pathophysiology. Inherited leukodystrophies also should be considered in the differential diagnosis, though their progressive nature would be atypical for pediatric-onset MS.
“Most cases of pediatric-onset MS occur post-puberty, so in cases of prepubertal presentation, it is essential to rule out other inflammatory diseases, especially MOGAD,” Hua said.
Diagnostic factors in late-onset MS differ from those in younger patients. Because older patients are more likely to experience subclinical small vessel disease, white matter hyperintensities on MRI could be misinterpreted as MS lesions, the expert committee pointed out.
“Late-onset MS can present with either relapses or progressive onset,” Hua observed. “The differential diagnosis depends on whether it’s an acute change or gradual worsening.”
Other disorders that affect the spinal cord — including neuromyelitis optica spectrum disorder, MOGAD, vitamin B12 deficiency, or cervical spondylosis — can mimic MS due to a progressive decline in walking, Hua noted. “Examining both the spinal cord and brain are important to determine if the cause is MS versus other diseases,” she said.
Higher proportions of the central vein sign are found in patients with MS compared with people who have mimics. The newly proposed McDonald diagnostic criteria revisions suggest that features like spinal cord lesions or the central vein sign be used to support MS diagnoses in people over age 50.
Paramagnetic rim lesions, also specific to MS in adults, differentiated pediatric MS from other inflammatory brain disorders in early evidence. Both the central vein sign and paramagnetic rim lesions can be obtained on a baseline scan to help with diagnosis, the expert panel suggested.
In older patients, a correct diagnosis is extremely important, committee members emphasized. The decision to start disease-modifying therapy is complicated by evidence suggesting disease-modifying treatments may be less effective with older age, and the risk of adverse effects increases.
In younger patients, starting high-efficacy therapy during childhood has been shown to reduce relapses and disability risk.
Better testing for genetic disorders with CNS manifestations may shape diagnostic approaches for pediatric or late-onset MS in the future, the panelists noted. Future research about MS differential diagnosis needs to include patients of diverse ages, they added.
Until sensitive and specific biomarkers are proven to confirm MS prior to its clinical manifestations, diagnosing MS in pediatric and adult populations with incidental MRI findings will “require a cohesive strategy for longitudinal observation,” they wrote.
Disclosures
Hua reported relationships with Genentech, Novartis, EMD Serono, TG Therapeutics, Horizon, and Alexion.
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